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Idiopathic Parkinson’s disease – pharmacological therapies
Idiopathic Parkinson’s disease requires pharmacological therapies alongside a surgical approach combined with physiotherapy, occupational therapy and speech and language therapy. The following are particularly useful: dancing, swimming, playing drums, yoga, tai chi, and qi gong. This review provides an overview of the potential for pharmacological therapies based on the guidelines of the Oesterreichische Parkinson Gesellschatt.
The aim of treatments for idiopathic Parkinson’s disease (IPD) is to control motor and non-motor symptoms (e.g. depression, autonomic failure, cognitive decline and unwanted therapy-induced side-effects). Reducing symptoms and complaints and maintaining everyday activities, social competence and occupational skills are the main targets of therapy.
This can be achieved by replacing the lack of the neurotransmitter dopamine with pro-drugs such as levodopa (l-3,4-dihydroxyphenylalanine), agonistic substances, non-dopaminergic but antiglutamatergic drugs such as amantadine, anticholinergic drugs and enzymes such as monoamine oxidase B (MAO-B) inhibitors and catechol-O-methyl transferase (COMT) inhibitors.
Levodopa (in combination with dopa decarboxylase and catechol-O-methyl transferase inhibitors)
Levodopa is the precursor of the neurotransmitter dopamine. Dopamine itself cannot pass the blood–brain barrier, but, given orally, levodopa can pass the barrier and is decarboxylated to dopamine in the basal ganglia. A lack of dopamine leads to the main symptoms of IPD such as akinesia, tremor and rigidity. Treatment with levodopa is still the gold standard of therapy 55 years after its introduction. It was first used to treat a patient in clinical practice by Birkmayer and Hornykiewicz,1 who published their findings in 1961 in Vienna. In certain circles this is not acknowledged, the first use of levodopa being instead being attributed to Cotzias2 in New York, but he did not publish his findings until 1967.
Orally administered levodopa has to reach the small intestine, where active transport through the wall of the gut into the blood takes place. A similar active transport system is used to pass the blood–brain barrier. It is important to explain this to patients, as for best results they must take the medication on an empty stomach with a large glass of water and should consume no protein for 30 minutes before or after taking the drug. En route to the brain, levodopa is broken down by enzymes such as dopa decarboxylase (DDC) and COMT. This is why levodopa always comes in preparations combined with DDC inhibitors (e.g. benserazide and carbidopa).
Dopamine is stored in presynaptic vesicles and is released into the synaptic cleft. These presynaptic stores diminish as the disease progresses and patients become dependent on an external supply of levodopa. As there is no longer any compensation from dopamine released from the vesicles, patients experience a ‘wearing off’ effect at the end of a course of the drug and a ‘boost’ on starting a new course.
A total daily dose of 200–800 mg taken four to six times throughout the day should give adequate control of symptoms (Table 1).
Levodopa has a clinical effect on all symptoms (akinesia, tremor, rigidity), as well as on some non-motor features of IPD. Although it half-life is only 90 minutes, it takes up to 14 days after washout until the effects of levodopa have completely worn off. This mechanism is known as a long-duration response and is not yet fully understood.
Currently, four non-ergot-derived drugs are used: oral pramipexole, ropinirole, transdermal rotigotine and subcutaneous apomorphine. The last is particularly effective because it is administered subcutaneously.
The main mode of action of the dopamine agonists is activation of the dopamine D2 receptor family. These drugs are easily absorbed in the small intestine and are less disrupted by food intake, as they are not competitively absorbed in the gut like levodopa. The orally administered dopamine agonists have a longer half-life than levodopa; transdermal rotigotine has a short half-life, but it is continuously absorbed transcutaneously.
Dopamine agonists improve all symptoms of IPD. Side-effects include fatigue, daytime sleepiness, ankle oedema, sometimes hallucinations and more often impulse control disorder (Table 2). This mainly presents as carbohydrate craving, gaming, excessive shopping, hypersexuality and punding (excessive pursuit of hobbies). Very often gaming and punding are combined in excessive use of computers and video games, leading to night-long sessions and increasing disturbance of the biorhythm. Before starting patients on dopamine agonists, it is essential to take a history of dependencies and other habits.
In the early years of development of the dopamine agonists, most preparations were ergotamine derivatives. However, this group of drugs was taken off the market because of severe side-effects, mainly fibrosis of the cardiac valves, although it had proved very useful for treatment of all symptoms of IPD.
Monoamine oxidase B inhibitors
This group consists of two substances: rasagiline is the most recently developed, but selegiline (also known as l-deprenyl) is still on the market, having been the first MAO-B inhibitor to be introduced in the 1970s. Both inhibit MAO-B, an enzyme that breaks down dopamine, thereby leading to increased levels and prolonged bioavailability of both intrinsically produced and ingested dopamine.
Selegiline (10 mg per day) and rasagiline (1 mg per day) are useful as monotherapy, as well as in combination with levodopa or dopamine agonists. The effect on clinical symptoms is much smaller than that of levodopa or dopamine agonists, but these drugs have additive effects. Moreover, they seem to result in a progressive deceleration of IPD.
Both in vivo and in vitro experiments have shown that these drugs have antiapoptotic effects (EVER Pharma GmbH, 2015, personal communication), which allows dopaminergic cells to survive longer. Therefore, these substances seem to have at least some cytoprotective effects.
Both drugs have a very long half-life of up to 40 days. This is important when starting therapy as well as when reducing the dose or discontinuing therapy because of side-effects. These are mainly of a dopaminergic nature (hypotension, sleepiness and hallucinations).
Serotonin syndrome may be induced if these drugs are used in combination with selective serotonin reuptake inhibitors, morphine and St John’s wort (Hypericum perforatum), a phytopharmacon, or herbal medicine, often used by patients as an antidepressant without their doctor’s knowledge.
Originally introduced as one of the first antiviral drugs, amantadine showed evidence of controlling the symptoms of IPD by chance as early as 1972. Since then, it has been the only substance available for parenteral use and treatment of akinetic crises. It releases dopamine and other catecholamines from presynaptic vesicles, and at higher doses it blocks catecholamine reuptake, modifies dopamine receptors and acts as an N-methyl-d-aspartate (NMDA) receptor blocker. As such, it is antiglutamatergic, glutamate being an antagonist of dopamine.
Amantadine has a positive influence on all motor functions (akinesia, tremor, rigidity), and it has a unique effect on levodopa-induced dyskinesias, making it irreplaceable in treating long-term side-effects.
Unfortunately, the drug may have side-effects such as constipation, urinary retention, hyperhidrosis, livedo reticularis, dry mouth, ankle oedema, nausea, headaches, ataxia and psychiatric problems, especially sleep disturbance, cognitive deficits and hallucinations.
Clinicians should bear in mind that in elderly people renal clearance may be impaired and an accumulation of the drug can cause severe side-effects.
Belladonna (Atropa belladonna) was first used in the nineteenth century for treating IPD. The mechanism of action is that it equilibrates the dopamine–acetylcholine imbalance in nigrostriatal pathways. Benzatropine also has a direct effect on dopamine reuptake. Clinical studies have shown the effectiveness of benzatropine, biperiden, bornaprine and procyclidine hydrochloride. Studies have also shown positive effects on resting and position tremor, akinesia, fine motor movements, mimic, rigidity and posture.3–6 The main indication is extrapyramidal resting tremor.
These drugs are normally well tolerated. Side-effects are anticholinergic (dry mouth, dry skin, tachycardia, increase in intraocular pressure and disturbance of accommodation (or ability to focus), constipation and urinary retention). In younger individuals, disorientation is seldom seen, whereas cognitive decline up to irreversible dementia can be deleterious in older individuals with the early stages of cortical deficits. Therefore anticholinergics need a very strict indication for their use.
The disease-oriented approach
Early idiopathic Parkinson’s disease
A valid diagnosis of IPD is essential. This sounds easier than it is because, to date, there are no valid biomarkers or imaging techniques that can prove a diagnosis of IPD. Clinicians still rely on experience and pharmacological testing (DOPA exposition, apomorphine test) to help secure the diagnosis.
Treatment should be started early in the course of the disease. There are no studies that show any advantage in delaying starting pharmacological treatment. As we can only treat the symptoms, the most disturbing are the parameters for prescribing the optimal drug or drugs. Quality of life and the patients’ professional requirements will determine the choice of drugs.
Rasagiline might be the first option. It is administered in a single dose of 1 mg once daily and is not normally associated with side-effects. It will control the less severe symptoms of IPD for a period of time. Increasing disability will lead to the prescription of dopamine agonists to gain more control of symptoms, especially in younger individuals. If the patient is over the age of 70, one would start with levodopa immediately, knowing that side-effects such as on–off fluctuations and dyskinesias are less common than in individuals with early-onset parkinsonism.
Amantadine might be an alternative in younger, cognitively stable, patients in order to postpone treatment with levodopa. A total daily dose of 100–300 mg in two or three intakes per day should not be exceeded.
As the disease progresses, first the dose of dopamine agonists will be increased, always aiming to keep the side-effects under control, particularly impulse control disorder. With only a single dose per day, patients may comply with treatment more readily.
Alternatively, levodopa will be administered, either with or without dopamine agonists. Different galenic preparations are available. Soluble levodopa preparations might act a little faster than normal tablets, and controlled-release capsules are meant to last a little longer, but in practice there is not too much difference. Drug regimens should be kept simple, because it is already complicated for patients to take all their prescribed medication at the correct time and with the precautions and conditions stipulated.
Levodopa has a short half-life: clinically it acts for up to 5 hours. It follows that four intakes per day will be necessary to maintain continuous dopaminergic stimulation.
The practical approach
Extrapyramidal resting tremor with a frequency of 4–6 Hz responds very well to dopaminergic treatment in most patients, levodopa also being the strongest medication for control of tremor. However, a minority of patients suffer from refractory tremor, although their akinesia and rigidity are well controlled. After trying various combinations of levodopa and dopamine agonists, anticholinergics may be necessary. People over the age of 60 should not be treated with anticholinergics, as they may experience cognitive deficits, sometimes irreversible.
Clozapine is another an option, but patients must have a white blood cell count every 2 weeks, as it can lead to leucopenia.
Finally, deep brain stimulation (DBS) is an effective alternative for control of tremor. See the state-of-the-art review on ‘Neuromodulation in Parkinson’s disease’ by François Alesch.
Fluctuations are the result of discontinuous dopaminergic stimulation resulting from the short half-life of levodopa and variable absorption in the small intestine. Therefore, it is useful to prescribe four intakes a day from the outset.
Wearing off is the most common manifestation of fluctuation, meaning that the symptoms relapse before the next drug intake is scheduled. Either more intakes at shorter intervals are necessary, or alternatively levodopa can be combined with a COMT inhibitor. The importance of strict adherence to the schedule must be explained to patients and caregivers.
Early morning and nightly ‘offs’ may respond well to an intake of a long-acting dopamine agonist in the evening or an early-morning intake of a soluble preparation of levodopa.
As a rescue medication, apomorphine can be administered subcutaneously. It acts within 15 minutes.
More severe fluctuations might be an indication for subcutaneous apomorphine or intrajejunal levodopa pump therapy or DBS.
Dyskinesias mostly manifest themselves as peak-dose dyskinesias an hour after intake of levodopa. Splitting the dose has the potential to control them.
Amantadine is the only oral antiparkinson medication with a direct antidyskinetic effect and an intrinsic antiparkinson effect. If tolerated, 300 mg per day is a very good option, as long as there are no side-effects.
Biphasic dyskinesias, which have a second peak at the end of a levodopa period, are not easily treated, although sometimes it helps to add a dopamine agonist with a long half-life or transdermal rotigotine.
Again subcutaneous apomorphine or intrajejunal levodopa pump therapy or DBS are good alternatives.
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Strang RR. Experiences with cogentin in the treatment of parkinsonism. A one–year controlled study of 94 patients. Acta Neurol Scand 1965; 41:413–18. http://dx.doi.org/10.1111/j.1600-0404.1965.tb04310.x
Friedman JH, Koller WC, Lannon MC, Busenbark K, Swanson-Hyland E, Smith D. Benztropine versus clozapine for the treatment of tremor in Parkinson’s disease. Neurology 1997; 48:1077–81. http://dx.doi.org/10.1212/WNL.48.4.1077
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